High resolution structural, functional and spectroscopic magnetic resonance (MR) imagings of the brain are powerful technologies for the study of epilepsy. Image-guided surgical resection has proven to be an effective treatment for many cases of medically intractable epilepsy. In neocortical, bilateral or otherwise diffuse epilepsy, however, localization of the epileptogenic region is more difficult and it is often impossible to surgically remove all of the potentially epileptogenic tissue due to its involvement in brain function. Responsive neurostimulation has emerged as a promising complementary technique for the treatment of epilepsy which can also serve as a powerful tool for interrogating brain function. We have been pursuing a program of MR imaging research on the study of localization related epilepsy and its response to two interventions: surgical resection and responsive neurostimulation. In the past 7 years of effort, we brought together internationally-recognized expertise in i.) neurosurgery/ neurology/electrophysiology, ii.) multiple disciplines of high field magnetic resonance, in particular, radiofrequency (rf) coil development, functional MRI, metabolic and spectroscopic MR and iii.) mathematical image analysis, via a group of six academic and two industrial partners. We developed and applied our methods to acquire and integrate multimodal magnetic resonance spectroscopic imaging (MRSI) and MRI information to enable better definition of neocortical epileptogenic substrates, enhance our understanding of the biochemical signatures underlying these substrates and differentiate these regions from normally functioning cortex. In this Competitive Revision, we propose to add a Yale PET imaging Partner to the BRP (lead by Dr. Richard Carson) and include high resolution FDG PET pre-interventional imaging using a high resolution HRRT scanner and perform validation against detailed electrical mapping of brain regions affected by seizure. Our goal is to integrate MRI, MRSI, and FDG-PET data to obtain higher specificity and sensitivity for localizing epileptogenic tissue and networks than any individual modality on its own. Relevance to Public Health: The understanding of the structure, function and metabolism of the normal and epileptogenic brain will add to the understanding of epilepsy in particular and neurodegenerative disease in general, ultimately helping to make appropriate interventional decisions. The ideas may lead to the definition of quantitative biomarkers that would help monitor progress in any one of several therapeutic interventions. PUBLIC HEALTH RELEVANCE: High resolution Magnetic Resonance structural and functional imaging (MRI), Magnetic Resonance Spectroscopic Imaging (MRSI) and Positron Emission Tomographic (PET) Imaging are powerful quantitative multidimensional imaging technologies that offer complimentary information about brain structure, function and metabolism. This information can be used to study longitudinal behavior of the brains of normal subjects and those with epilepsy in an integrated manner. As part of our existing BRP we have been developing, validating, and integrating quantitative information from multiple imaging modalities to study epilepsy with the goals of guiding surgery and tracking progress during therapeutic treatment. In the work proposed in this supplement we will add ultra high resolution quantitative FDG-PET to the armamentarium of biomarkers and assess its effectiveness in improving the sensitivity and specificity of identifying epileptogenic tissue and networks by imaging. We anticipate these developments will apply to a wide range of neurological disorders.